Le aspettative presenti e future

Transcript

1 Le aspettative presenti e future Armando D Angelo Servizio di Coagulazione ed Unità Ricerca Trombosi, OSR, Milano 2nd Pavia Spring Meeting on Thrombosis I Nuovi Anticoagulanti Orali Diretti nella Gestione del Tromboembolismo: Aspetti Clinici e di Laboratorio Pavia, venerdì 13 giugno 2014

2 Warfarin

3 Events / 1000 patient years Narrow therapeutic range with VKA 80 Target INR ( ) Ischaemic stroke Intracranial haemorrhage The anticoagulant effect of vitamin K antagonists are optimized when therapeutic doses are maintained within a very narrow range 0 < > Hylek EM, et al. N Eng J Med 2003; 349: International Normalised Ratio (INR)

4 Warfarin

5 New oral anticoagulants Rivaroxaban Apixaban Edoxaban Dabigatran

6 Non valvular atrial fibrillation Dabi LD Dabi HD Riva SD Apix SD Edox LD Edox HD Stroke/SE ni* -33% ni -20% ni ni * Non inferior; -21% on treatment

7 Non valvular atrial fibrillation Dabi LD Dabi HD Riva SD Apix SD Edox LD Edox HD Stroke/SE ni* -33% ni -20% ni ni Non hemorrh. stroke ni -23% ni ni +42% ni * Non inferior; -21% on treatment

8 Non valvular atrial fibrillation Dabi LD Dabi HD Riva SD Apix SD Edox LD Edox HD Stroke/SE ni* -33% ni -20% ni ni Non hemorrh. stroke ni -23% ni ni +42% ni Hemorrhagic stroke -69% -74% -42% -49% -67% -46% * Non inferior; -21% on treatment

9 Non valvular atrial fibrillation Dabi LD Dabi HD Riva SD Apix SD Edox LD Edox HD Stroke/SE ni* -33% ni -20% ni ni Non hemorrh. stroke ni -23% ni ni +42% ni Hemorrhagic stroke -69% -74% -42% -49% -67% -46% Intracranial bleeding -69% -59% -34% -58% -69% -54% * Non inferior; -21% on treatment

10 Non valvular atrial fibrillation Dabi LD Dabi HD Riva SD Apix SD Edox LD Edox HD Stroke/SE ni* -33% ni -20% ni ni Non hemorrh. stroke ni -23% ni ni +42% ni Hemorrhagic stroke -69% -74% -42% -49% -67% -46% Intracranial bleeding -69% -59% -34% -58% -69% -54% Fatal bleeding -42% -27% -50% -38% -65% -45% * Non inferior; -21% on treatment

11 Non valvular atrial fibrillation Dabi LD Dabi HD Riva SD Apix SD Edox LD Edox HD Stroke/SE ni* -33% ni -20% ni ni Non hemorrh. stroke ni -23% ni ni +42% ni Hemorrhagic stroke -69% -74% -42% -49% -67% -46% Intracranial bleeding -69% -59% -34% -58% -69% -54% Fatal bleeding -42% -27% -50% -38% -65% -45% Vascular death ni -15% ni ni -15% -14% * Non inferior; -21% on treatment

12 Non valvular atrial fibrillation Dabi LD Dabi HD Riva SD Apix SD Edox LD Edox HD Stroke/SE ni* -33% ni -20% ni ni Non hemorrh. stroke ni -23% ni ni +42% ni Hemorrhagic stroke -69% -74% -42% -49% -67% -46% Intracranial bleeding -69% -59% -34% -58% -69% -54% Fatal bleeding -42% -27% -50% -38% -65% -45% Vascular death ni -15% ni ni -15% -14% All-cause death ni ni ni ni -13% ni * Non inferior; -21% on treatment; p = 0.051

13 Non valvular atrial fibrillation Dabi LD Dabi HD Riva SD Apix SD Edox LD Edox HD Stroke/SE ni* -33% ni -20% ni ni Non hemorrh. stroke ni -23% ni ni +42% ni Hemorrhagic stroke -69% -74% -42% -49% -67% -46% Intracranial bleeding -69% -59% -34% -58% -69% -54% Fatal bleeding -42% -27% -50% -38% -65% -45% Vascular death ni -15% ni ni -15% -14% All-cause death ni ni ni ni -13% ni * Non inferior; -21% on treatment; p = 0.051

14 Un confronto con i pazienti dei Centri Emostasi e Trombosi

15 Major bleeding complications DABI EDOX RIVA APIX LD HD LD HD SD SD % p-y % p-y % p-y % p-y % p-y % p-y Mean age (yrs) Major bleeding Intracranial bleeding Gastrointestinal bleeding Fatal bleeding

16 Major bleeding complications DABI EDOX RIVA APIX AVK LD HD LD HD SD SD Poli et al % p-y % p-y % p-y % p-y % p-y % p-y % p-y Mean age (yrs) Major bleeding Intracranial bleeding Gastrointestinal bleeding Fatal bleeding

17 Ma

18

19 Perché meno emorragie intracraniche?

20 Proteine vitamina K-dipendenti Matrix Gla-protein ed osteocalcina Minor numero di emorragie cerebrali Osteoprosi

21 Vantaggi dei nuovi farmaci anticoagulanti orali Riduzione delle emorragie intracraniche Risparmio del sistema della proteina C Scompare la necrosi cutanea da AVK

22 Vantaggi dei nuovi farmaci anticoagulanti orali Riduzione delle emorragie intracraniche Risparmio del sistema della proteina C Scompare la necrosi cutanea da AVK Si riducono gli stroke cardioembolici ad inizio di trattamento?

23 Increased risk of stroke and of bleeding events on transitioning from Rivaroxaban or Apixaban to Warfarin HR for ischemic stroke/embolism Rivaroxaban Apixaban to W to W

24 Increased risk of stroke and of bleeding events on transitioning from Rivaroxaban or Apixaban to Warfarin HR for ischemic stroke/embolism HR for major bleeding events Rivaroxaban to W* Apixaban to W * less than 50% of patients had a therapeutic INR 30 days after last dose of rivaroxaban

25 This pattern mirrored the first 30 days of the trial where warfarin-naive patients starting warfarin had a higher rate of stroke or systemic embolism (5.41 % pat-y) than warfarin-experienced patients (1.41 % pat-y).

26 Azoulay L, et ai. Eur Heart J, December 18, 2013 Using the UK Clinical Practice Research Datalink, a nested case control analysis was conducted within a cohort of 70,766 patients with AF between 1993 and Stroke cases were randomly matched with up to 10 controls on age, sex, date of AF diagnosis, and time since AF diagnosis. Conditional logistic regression was used to estimate adjusted rate ratios (RRs) with 95% confidence intervals (CIs) of stroke associated with current warfarin use classified according to time since initiation of treatment (<30 days, days, and >90 days), when compared with non-use.

27 Azoulay L et al. Eur Heart J 2013;eurheartj.eht499 Study flow chart.

28 Azoulay L, et ai. Eur Heart J, December 18, 2013

29 Azoulay L, et ai. Eur Heart J, December 18, 2013

30 Azoulay L, et ai. Eur Heart J, December 18, 2013 A total of 5519 patients experienced a stroke during follow-up. Warfarin was associated with a 71% increased risk of stroke in the first 30 days of use: RR: 1.71, 95% CI: ), while decreased risks were observed with initiation >30 days before the event days: RR: 0.50, 95% CI: >90 days: RR: 0.55, 95% CI:

31 INR (---) 5 warfarin TIME (hours)

32 INR (---) 5 warfarin F1+2, nmol/l ( ) TIME (hours)

33 FACTOR LEVELS, % 100 warfarin FII 25 FVII FX 0 TIME (hours)

34 FACTOR LEVELS, % 100 warfarin FII 25 PC 0 TIME (hours)

35 Smooth cubic spline curve of the adjusted rate ratio of ischaemic stroke (solid line) and 95% confidence limits (dashed lines) as a function of the time since initiation of warfarin. Azoulay L et al. Eur Heart J 2013;eurheartj.eht499

36 Azoulay L, et ai. Eur Heart J, December 18, 2013 Patients initiating warfarin may be at an increased risk of stroke during the first 30 days of treatment, supporting the biological plausibility of a transient hypercoagulable state at the start of the treatment, although additional studies are needed to confirm these findings.

37 FVII, % of baseline Warfarin treatment mg 10 mg 30, 20, 10 mg Time (days)

38 PC, % of baseline FVII, % of baseline Warfarin treatment mg 10 mg 30, 20, 10 mg Time (days) 5 mg 10 mg 30, 20, 10 mg Time (days)

39 PC, % of baseline FVII, % of baseline FX, % of baseline Warfarin treatment mg 10 mg 30, 20, 10 mg Time (days) 5 mg 10 mg 30, 20, 10 mg Time (days) mg 10 mg 30, 20, 10 mg Time (days)

40 PC, % of baseline FII, % of baseline FVII, % of baseline FX, % of baseline Warfarin treatment mg 10 mg 30, 20, 10 mg Time (days) mg 10 mg 30, 20, 10 mg Time (days) mg 10 mg 30, 20, 10 mg INR Time (days) Time (days)

41 D Angelo A, et al. Eur Heart J, January 15, 2014 The INR is a valid monitoring tool in patients on stable VKA treatment because it adjusts for the different sensitivity of thromboplastin reagents to the reduction in factor II, but this is not true at initiation of VKA treatment because of the much faster reduction in factor VII levels. Hence, the faster obtainment of "therapeutic" INRs with a loading dose is meaningless with respect to antithrombotic activity.

42 D Angelo A, et al. Eur Heart J, January 15, 2014 The INR is a valid monitoring tool in patients on stable VKA treatment because it adjusts for the different sensitivity of thromboplastin reagents to the reduction in factor II, but this is not true at initiation of VKA treatment because of the much faster reduction in factor VII levels. Hence, the faster obtainment of "therapeutic" INRs with a loading dose is meaningless with respect to antithrombotic activity. Based on data from patients with acute VTE - and heparin bridging -, the 2012 ACCP guidelines suggest (grade 2C) initiating therapy with warfarin 10 mg for the first two days rather than starting with the estimated maintenance dose.

43 D Angelo A, et al. Eur Heart J, January 15, 2014 The INR is a valid monitoring tool in patients on stable VKA treatment because it adjusts for the different sensitivity of thromboplastin reagents to the reduction in factor II, but this is not true at initiation of VKA treatment because of the much faster reduction in factor VII levels. Hence, the faster obtainment of "therapeutic" INRs with a loading dose is meaningless with respect to antithrombotic activity. Based on data from patients with acute VTE - and heparin bridging -, the 2012 ACCP guidelines suggest (grade 2C) initiating therapy with warfarin 10 mg for the first two days rather than starting with the estimated maintenance dose. The implication of a 2C suggestion is that higher-quality research may well change the estimate: isn't it time for a change?

44 Lo scenario della scelta Pazienti con reale difficoltà al monitoraggio di laboratorio con gli AVK Pazienti con emorragia maggiore durante AVK Pazienti con INR labile Pazienti ad alto rischio emorragico (HASBLED) Pazienti con episodi embolici in range terapeutico con AVK Pazienti con episodi embolici da porre in terapia anticoagulante (alto rischio embolico)??? Tutti i nuovi pazienti che necessitano terapia anticoagulante Pazienti naive che preferiscano i DOAC agli AVK Pazienti in AVK che preferiscano evitare il monitoraggio di laboratorio Pazienti con episodi embolici durante terapia con AVK

45 Lo scenario della scelta Pazienti con reale difficoltà al monitoraggio di laboratorio con gli AVK Pazienti con emorragia maggiore durante AVK Pazienti con INR labile Pazienti ad alto rischio emorragico (HASBLED) Pazienti con episodi embolici in range terapeutico con AVK Pazienti con episodi embolici da porre in terapia anticoagulante (alto rischio embolico)??? Tutti i nuovi pazienti che necessitano terapia anticoagulante Pazienti naive che preferiscano i DOAC agli AVK Pazienti in AVK che preferiscano evitare il monitoraggio di laboratorio Pazienti con episodi embolici durante terapia con AVK

46 Ostacoli potenziali ai nuovi farmaci Mancanza di antidoti

47 Ostacoli potenziali ai nuovi farmaci Mancanza di antidoti Aderenza e persistenza senza monitoraggio di laboratorio

48 Osterberg L, Blaschke T. Adherence to medication NEJM 2005;353;487

49

50 Ostacoli potenziali ai nuovi farmaci Mancanza di antidoti Aderenza e persistenza senza monitoraggio di laboratorio Il paradigma dell ampio range terapeutico non è piuttosto solo ampia variabilità interindividuale?

51 Steady state plasma concentrations of DOACs (ng/ml) Dabigatran Rivaroxaban Apix Stroke prevention in NVAF Cmax 126; (10-90 perc) [110 mg]?? 175; (10-90 perc) [150 mg] Ctrough 65; (10-90 perc) [110 mg] 91; (10-90 perc) [150 mg]?? Treatment and secondary prevention of VTE Cmax 215; (10-90 perc)? Ctrough 32; (10-90 perc)?

52 Dabigatran trough concentrations, ng/ml (10-16 h after dosing) Reilly PA, et al. JACC 2014;63: % 3.8% 27.2% 69.0% Hemorrhagic stroke Major bleeding Any bleeding No bleeding

53 OR OR Reilly PA, et al. JACC 2014;63:321-8 Major Bleeding Stroke/SE

54 OR OR Reilly PA, et al. JACC 2014;63:321-8 Major Bleeding Stroke/SE

55 Reilly PA, et al. JACC 2014;63: year old male AF patient with diabetes and prior stroke (10th and 90th percentile)

56 Events / 1000 patient years Narrow therapeutic range with VKA in AF/VTE 80 Target INR ( ) Ischaemic stroke Intracranial haemorrhage The anticoagulant effect of vitamin K antagonists are optimized when therapeutic doses are maintained within a very narrow range 0 < > Hylek EM, et al. N Eng J Med 2003; 349: International Normalised Ratio (INR)

57 Perché non usare il laboratorio per valutare l attività anticoagulante dei dei nuovi farmaci e garantire maggiore sicurezza ai pazienti?

58 Migliorare efficacia e sicurezza?

59 Non è difficile

60 DOA: QUALI TEST? FARMACO Dabigatran (ng/ml) Rivaroxaban (ng/ml) Apixaban (ng/ml) Edoxaban (ng/ml) DOSAGGIO DELL ATTIVITA ANTICOAGULANTE dtt ECT /ECA axa Pengo V et al, T&H 2011; Douxfils J et al, T&H 2012, 2013; Baglin T, JT&H 2013.

61 Tempo di trombina diluito, sec Concentrazione osservata, ng/ml Misurare la concentrazione plasmatica di dabigatran con il tempo di trombina diluito (mediana di concentrazione attesa a valle 91 ng/ml) % 4.9% % % % % 2.7% % % % 2.4% 5.0% Dabigatran, ng/ml Concentrazione attesa, ng/ml

62 mabs, 405 nm Concentrazione osservata, ng/ml Misurare la concentrazione plasmatica di rivaroxaban con il test anti-xa (mediana di concentrazione attesa a valle 32 ng/ml) % 2.3% 2.6% 2.9% 3.9% 4.4% Rivaroxaban, ng/ml Concentrazione attesa, ng/ml % 2.0% 1.8% 3.7% 5.7%

63 mabs, 405 nm Concentrazione osservata, ng/ml Misurare la concentrazione plasmatica di apixaban con il test anti-xa (mediana di concentrazione attesa a valle?) % 1.5% 1.7% 1.9% 1.8% 2.5% % 2.0% 1.4% 1.8% 1.4% 0.6% Apixaban, ng/ml Concentrazione attesa, ng/ml

64 Il rivedere i pazienti ad intervalli regolari, misurandone le concentrazioni di farmaco, costituisce anche un supporto educazionale importante per la loro aderenza/persistenza alla terapia anticoagulante

65 Anticoagulation clinics Hospital pharmacies Hemostasis and Thrombosis Centers (certified) Pharmacovigilance (AIFA, START registry) NOACS specific testing Research Pharmaceutical Companies Involvment of GPs in patient follow up Prescription of NOACS together with Specialists in Internal Medicine, Cardiology, Neurology, Hematology, Geriatrics